Regulatory T cells (Treg) are one of the major impediments to effective antitumor immunity and successful immunotherapy. Elevated intratumoral Treg frequencies, observed in a variety of malignancies, have been associated with poor prognosis. In this issue of Cancer Research, two studies underscore the potential of harnessing the unique migratory profile of tumor-infiltrating Tregs to selectively eliminate these cells without compromising peripheral tolerance. Both studies identify surface migratory receptors, CCR8 by Campbell and colleagues and GPR15 by Adamczyk and colleagues, as selective markers of intratumoral Tregs in tumor-bearing mice and patients with cancer. Genetic deletion of GPR15 or antibody-mediated depletion of CCR8 was found to preferentially decrease tumor-infiltrating Tregs and substantially delayed tumor progression. Together, these two studies highlight the significance of migratory molecules in intratumoral Tregs and propose two potential selective targets for preferential elimination of tumor-associated "pathogenic" Tregs, which can be hijacked to enhance the response to immunotherapy.See related articles by Adamczyk et al., p. 2970 and Campbell et al., p. 2983.